Abstract There are 100 million people living with chronic pain in the U.S., which is more than the combined prevalence of cancer, diabetes and heart disease. Chronic pain is the number one cause of long-term disability in the U.S.. To make matters worse, the prolific use of opioids to treat chronic pain has exacerbated drug abuse and addiction, placing opioid painkillers at the heart of a raging crisis that took 42,000 American lives in 2016. To curb the opioid crisis, the president declared a public-health emergency while state lawmakers and various health systems started putting measures in place to cap the number of opioids prescribed by doctors. Although these measures have coincided with 22% reductions in opioid prescriptions in recent years, this leaves Americans suffering from chronic pain with few if any effective option. There is a significant and urgent need of alternative pain treatment. Capsaicin is a plant-derived spice and medicine that has been formulated as an analgesic in topical ointments and dermal patches to relieve pain. The therapeutic effect is achieved by targeting the transient receptor potential vanilloid 1 (TRPV1), thereby inactivating neurological pathways that transmit pain signals. Despite the promissory medicinal potential, the inherent pungency and hydrophobicity severely restrict the effectiveness and application of capsaicin as an analgesic drug. It is of great importance to test the hypothesis that the TRPV1 activity of capsaicin can be separated from the pungency and hydrophobicity. Building on our core expertise in synthesizing and improving bioactive natural products as drug candidates, Young BioPharma is dedicated to fighting the opioid crisis by developing safe and efficacious, nature product-based therapies for the treatment of chronic pain. Through our medicinal chemistry effort, we rectified the wrong SAR conclusions from the literature reports, confirmed the hypothesis and discovered a novel compound YB-2 with potent in vitro TRPV1 modulatory activity, low pungency and high aqueous solubility. We believe this promising agent is an ideal candidate for further development. Instead of being confined by inefficient topical use at low concentration like capsaicin due to pungency and hydrophobicity, YB-2 can be employed at much higher dose in clinical trials through more effective i.v. and oral administrations. Thus, it will be much easier to achieve therapeutic endpoints. With a favorable therapeutic profile, YB-2 opens up a brand-new paradigm as a potential game-changing analgesic therapy, providing millions of patients with alternative safe and efficacious pain treatment. The overall objective of this proposal is to develop novel TRP modulator YB-2 to fight opioid crisis and treat chronic pain. In order to advance this therapeutic towards the IND application with the FDA, within 12 months we aim to synthesize 1 g of YB-2, confirm the in vitro activity, test YB-2 in three animal models of pain via i.v. and oral administrations, and conduct DMPK studies. We consider phase I successful if YB-2 can demonstrate in vivo efficacy in at least 2 of the 3 animal models without significant side effect.